Sertraline hydrochloride, (1S-cis)-4-(3,4 dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride, having the formula:
is approved, under the trademark Zoloft®, by the U.S. Food and Drug Administration, as a serotonin re-uptake inhibitor for the treatment of depression, obsessive-compulsive disorder, panic disorder and post-traumatic disorder. Only S-cis sertraline is therapeutically active.
U.S. Pat. No. 4,536,518 describes a synthesis of sertraline hydro chloride from sertralone having the following formula:

The process for synthesizing sertraline from sertralone has two steps. First, sertralone is condensed with methyl amine in the presence of an acid catalyst, to yield the Schiff base of sertralone, “sertraline-1-imine”:

The imine is then reduced to sertraline. The reduction process of U.S. Pat. No. 4,536,518 involves the hydrogenation of sertraline-1-imine concentrate at room temperature for two hours over 10% Pd/C catalyst in an atmosphere of hydrogen (1 atm pressure). The product is a racemic mixture of the cis and trans diastereoisomers (“(±)-cis/trans-sertraline”) in the ratio of approximately 3 to 1. The '518 patent discloses that reduction with NaBH4 gives a cis:trans ratio of about 1:1.
As illustrated in the process of the '518 patent, a problem with synthesis of sertraline is the formation of useless stereoisomers which decrease the overall yield. Due to presence of two chiral centers, at C-1 and C-4 (C-4 refers to the carbon next to the dichlorobenzyl group), four different stereoisomers are produced during the synthesis process. Of these, one is sertraline (cis-1S, 4S), and its enantiomer (cis-1R, 4R). The other are trans stereoisomers (1R, 4S) and (1S, 4R).
Sertraline may be isolated in two ways from the other stereoisomers. Isolation of sertraline from the its trans stereoisomers may be done in a classical way by crystallization since distereoisomers have substantially different characteristics. Isolation of sertraline from its enantiomer 1R, 4R-Sertraline may be done by selective precipitation with a chiral entity such as mandelic acid.
U.S. Pat. No. 5,082,970, according to its abstract, discloses a process for converting trans-isomeric sertraline to cis-isomeric sertraline by contacting trans-sertraline, or a mixture of same with up to about an equal part by weight of the corresponding cis-isomer, with a basic equilibration agent like potassium t-butoxide in a reaction-inert polar organic solvent to ultimately afford a cis/trans-mixture wherein the amount of cis-amine present in the mixture achieves a constant value of about 2:1 on a weight-by-weight basis.
WO 01/49638, according to its abstract, discloses a process for converting the cis (1R, 4R), trans (1S, 4R), and trans (1R, 4S) stereoisomers of sertraline into sertraline, starting with an initial reaction mixture which contains at least one of these stereoisomers and converting the sertraline stereoisomers into an imine form of sertraline. The imine form of sertraline is then reduced so that sertraline and at least one sertraline stereoisomer byproduct is produced in the reaction mixture. The sertraline is then recovered from the reaction mixture, e.g., by fractional crystallization (followed by resolution of sertraline from the cis (1R, 4R) stereoisomer, if necessary). The reaction mixture is then recycled through the same steps so that sertraline is produced from its stereoisomers in an asymptotic yield. The reaction scheme of WO 01/49638 requires conversion to an imine before isomerization.
WO 97/21662, according to its abstract, provides a process for racemising an optically-enriched chiral amine of the formula: R1-CH(NR3R4)-R2, wherein R1 is aromatic or unsaturated alkyl; R2 is aromatic or alkyl; and R3 and R4 are independently selected from hydrogen, alkyl and aryl; and wherein any combination(s) of two of the R groups may form a ring; comprises treatment of the optically-enriched amine with a metal hydroxide in an aprotic polar solvent. However, the present Applicants could not isomerize sertraline stereoisomers when carrying out the process of WO 97/21662.
There is a need in the art for recylcing processes which produce sertraline economically on an industrial scale.